tbuckley/cabot-search huggingface dataset:
Identifying novel mechanisms of biallelic TP53 loss refines poor outcome for patients with multiple myeloma
Authors: Enze Liu, Parvathi Sudha, Nathan Becker, Oumaima Jaouadi, Attaya Suvannasankha, Kelvin Lee, Rafat Abonour, Mohammad Abu Zaid, Brian A. Walker
Journal: Blood Cancer Journal (2023)

Biallelic TP53 inactivation is the most important high-risk factor associated with poor survival in multiple myeloma. Classical biallelic TP53 inactivation has been defined as simultaneous mutation and copy number loss in most studies; however, numerous studies have demonstrated that other factors could lead to the inactivation of TP53. Here, we hypothesized that novel biallelic TP53 inactivated samples existed in the multiple myeloma population. A random forest regression model that exploited an expression signature of 16 differentially expressed genes between classical biallelic TP53 and TP53 wild-type samples was subsequently established and used to identify novel biallelic TP53 samples from monoallelic TP53 groups. The model reflected high accuracy and robust performance in newly diagnosed relapsed and refractory populations. Patient survival of classical and novel biallelic TP53 samples was consistently much worse than those with mono-allelic or wild-type TP53 status. We also demonstrated that some predicted biallelic TP53 samples simultaneously had copy number loss and aberrant splicing, resulting in overexpression of high-risk transcript variants, leading to biallelic inactivation. We discovered that splice site mutation and overexpression of the splicing factor MED18 were reasons for aberrant splicing. Taken together, our study unveiled the complex transcriptome of TP53, some of which might benefit future studies targeting abnormal TP53.
Treatment of older adults with FLT3-mutated AML: Emerging paradigms and the role of frontline FLT3 inhibitors
Authors: Nicholas J. Short, Daniel Nguyen, Farhad Ravandi
Journal: Blood Cancer Journal (2023)

Abstract FLT3 is the most frequently mutated gene in acute myeloid leukemia (AML), with FLT3 internal tandem duplication (ITD) mutations being associated with a more aggressive clinical course. While two large, randomized clinical trials have shown a survival benefit with the frontline use of an oral FLT3 inhibitor (midostaurin or quizartinib) in patients with FLT3 -mutated AML, the role of FLT3 inhibitors in older adults with newly diagnosed FLT3 -mutated AML remains unclear. A definitive improvement in survival has not been observed in intensively treated patients over 60 years of age receiving frontline FLT3 inhibitors. Furthermore, many patients with FLT3 -mutated AML are unsuitable for intensive chemotherapy due to age and/or comorbidities, and this population represents a particular unmet need. For these older patients who are unfit for intensive approaches, azacitidine + venetoclax is a new standard of care and is used by many clinicians irrespective of FLT3 mutation status. However, FLT3 -ITD mutations confer resistance to venetoclax and are a well-established mechanism of relapse to lower-intensity venetoclax-based regimens, leading to short durations of remission and poor survival. Preclinical and clinical data suggest synergy between FLT3 inhibitors and venetoclax, providing rationale for their combination. Novel strategies to safely incorporate FLT3 inhibitors into the standard hypomethylating agent + venetoclax backbone are now being explored in this older, less fit population with newly diagnosed FLT3 -mutated AML, with encouraging early results. Herein, we discuss the frontline use of FLT3 inhibitors in older adults with FLT3 -mutated AML, including the potential role of FLT3 inhibitors in combination with intensive chemotherapy and as part of novel, lower-intensity doublet and triplet regimens in this older population.
Development and validation of an accurate smartphone application for measuring waist-to-hip circumference ratio
Authors: Siddharth Choudhary, Ganesh Iyer, Brandon M. Smith, Jinjin Li, Mark Sippel, Antonio Criminisi, Steven B. Heymsfield
Journal: npj Digital Medicine (2023)

Waist-to-hip circumference ratio (WHR) is now recognized as among the strongest shape biometrics linked with health outcomes, although use of this phenotypic marker remains limited due to the inaccuracies in and inconvenient nature of flexible tape measurements when made in clinical and home settings. Here we report that accurate and reliable WHR estimation in adults is possible with a smartphone application based on novel computer vision algorithms. The developed application runs a convolutional neural network model referred to as MeasureNet that predicts a person's body circumferences and WHR using front, side, and back color images. MeasureNet bridges the gap between measurements conducted by trained professionals in clinical environments, which can be inconvenient, and self-measurements performed by users at home, which can be unreliable. MeasureNet's accuracy and reliability is evaluated using 1200 participants, measured by a trained staff member. The developed smartphone application, which is a part of Amazon Halo, is a major advance in digital anthropometry, filling a long-existing gap in convenient, accurate WHR measurement capabilities.
Zanubrutinib: past, present, and future
Authors: Constantine S. Tam, Javier L. Muñoz, John F. Seymour, Stephen Opat
Journal: Blood Cancer Journal (2023)

Abstract In recent years, Bruton tyrosine kinase (BTK) inhibitors have provided significant advances in the treatment of patients with B-cell malignancies. Ibrutinib was the first BTK inhibitor to be approved, and it changed the standard-of-care treatment for diseases such as chronic lymphocytic leukemia, mantle cell lymphoma, marginal zone lymphoma, and Waldenström macroglobulinemia, improving efficacy outcomes and safety compared to chemotherapy. In this article, we review the development of zanubrutinib, a next-generation BTK inhibitor, from molecular design to patient-related outcomes. We start this journey by providing insights into the discovery of BTK and the physiologic, genetic, and molecular characterization of patients lacking this kinase, together with the brief treatment landscape in the era of chemo-immunotherapies. Zanubrutinib was originally developed by applying a structure-activity strategy to enhance the specificity as well as enzymatic and pharmacokinetic properties. Preclinical studies confirmed greater specificity and better bioavailability of zanubrutinib compared with that of ibrutinib, which supported the initiation of clinical trials in humans. Preliminary clinical results indicated activity in B-cell malignancies together with an improved safety profile, in line with less off-target effects described in the preclinical studies. The clinical program of zanubrutinib has since expanded significantly, with ongoing studies in a wide range of hemato-oncological diseases and in combination with many other therapies. Zanubrutinib currently is approved for various B-cell malignancies in multiple countries. This story highlights the importance of multidisciplinary collaborative research, from bench to bedside, and provides an example of how the commitment to finding improved treatment options should always run parallel to patient care.
The International Association for the Study of Lung Cancer Thymic Epithelial Tumors Staging Project: An Overview of the Central Database Informing Revision of the Forthcoming (Ninth) Edition of the TNM Classification of Malignant Tumors
Authors: Andreas Rimner, Enrico Ruffini, Vanessa Cilento, Emily Goren, Usman Ahmad, Sarit Appel, Andrea Bille, Souheil Boubia, Cecilia Brambilla, Ayten Kayi Cangir, Frank Detterbeck, Conrad Falkson, Wentao Fang, Pier Luigi Filosso, Giuseppe Giaccone, Nicolas Girard, Francesco Guerrera, James Huang, Maurizio Infante, Dong Kwan Kim, Marco Lucchi, Mirella Marino, Edith M. Marom, Andrew G. Nicholson, Meinoshin Okumura, Ramon Rami-Porta, Charles B. Simone, Hisao Asamura
Journal: Journal of Thoracic Oncology (2023)
Theratyping cystic fibrosis patients to guide elexacaftor/tezacaftor/ivacaftor out-of-label prescription
Authors: Elise Dreano, Pierre Régis Burgel, Aurelie Hatton, Naim Bouazza, Benoit Chevalier, Julie Macey, Sylvie Leroy, Isabelle Durieu, Laurence Weiss, Dominique Grenet, Nathalie Stremler, Camille Ohlmann, Philippe Reix, Michele Porzio, Pauline Roux Claude, Natacha Rémus, Benoit Douvry, Sylvie Montcouquiol, Laure Cosson, Julie Mankikian, Jeanne Languepin, Veronique Houdouin, Laurence Le Clainche, Anne Guillaumot, Delphine Pouradier, Adrien Tissot, Pascaline Priou, Laurent Mély, Frederique Chedevergne, Muriel Lebourgeois, Jean Lebihan, Clémence Martin, Flora Zavala, Jennifer Da Silva, Lydie Lemonnier, Mairead Kelly-Aubert, Anita Golec, Pierre Foucaud, Christophe Marguet, Aleksander Edelman, Alexandre Hinzpeter, Paola de Carli, Emmanuelle Girodon, Isabelle Sermet-Gaudelus, Iwona Pranke
Journal: European Respiratory Journal (2023)

Around 20% of people with cystic fibrosis (pwCF) do not have access to the triple combination elexacaftor/tezacaftor/ivacaftor (ETI) in Europe because they do not carry the F508del allele on the CF transmembrane conductance regulator (CFTR) gene. Considering that pwCF carrying rare variants may benefit from ETI, including variants already validated by the US Food and Drug Administration (FDA), a compassionate use programme was launched in France. PwCF were invited to undergo a nasal brushing to investigate whether the pharmacological rescue of CFTR activity by ETI in human nasal epithelial cell (HNEC) cultures was predictive of the clinical response.CFTR activity correction was studied by short-circuit current in HNEC cultures at basal state (dimethyl sulfoxide (DMSO)) and after ETI incubation and expressed as percentage of normal (wild-type (WT)) CFTR activity after sequential addition of forskolin and Inh-172 (ΔIETI/DMSO%WT).11 pwCF carried variants eligible for ETI according to the FDA label and 28 carried variants not listed by the FDA. ETI significantly increased CFTR activity of FDA-approved CFTR variants (I601F, G85E, S492F, M1101K, R347P, R74W;V201M;D1270N and H1085R). We point out ETI correction of non-FDA-approved variants, including N1303K, R334W, R1066C, Q552P and terminal splicing variants (4374+1G>A and 4096-3C>G). ΔIETI/DMSO%WT was significantly correlated to change in percentage predicted forced expiratory volume in 1 s and sweat chloride concentration (p<0.0001 for both). G85E, R74W;V201M;D1270N, Q552P and M1101K were rescued more efficiently by other CFTR modulator combinations than ETI.Primary nasal epithelial cells hold promise for expanding the prescription of CFTR modulators in pwCF carrying rare mutants. Additional variants should be discussed for ETI indication.
Author Correction: Commensal bacteria weaken the intestinal barrier by suppressing epithelial neuropilin-1 and Hedgehog signaling
Authors: Giulia Pontarollo, Bettina Kollar, Amrit Mann, My Phung Khuu, Klytaimnistra Kiouptsi, Franziska Bayer, Inês Brandão, Valeriya V. Zinina, Jennifer Hahlbrock, Frano Malinarich, Maximilian Mimmler, Sudhanshu Bhushan, Federico Marini, Wolfram Ruf, Meriem Belheouane, John F. Baines, Kristina Endres, Scott M. Reba, Verena K. Raker, Carsten Deppermann, Christoph Welsch, Markus Bosmann, Natalia Soshnikova, Benoit Chassaing, Mattias Bergentall, Felix Sommer, Fredrik Bäckhed, Christoph Reinhardt
Journal: Nature Metabolism (2023)
Artificial intelligence for natural product drug discovery
Authors: Michael W. Mullowney, Katherine R. Duncan, Somayah S. Elsayed, Neha Garg, Justin J. J. van der Hooft, Nathaniel I. Martin, David Meijer, Barbara R. Terlouw, Friederike Biermann, Kai Blin, Janani Durairaj, Marina Gorostiola González, Eric J. N. Helfrich, Florian Huber, Stefan Leopold-Messer, Kohulan Rajan, Tristan de Rond, Jeffrey A. van Santen, Maria Sorokina, Marcy J. Balunas, Mehdi A. Beniddir, Doris A. van Bergeijk, Laura M. Carroll, Chase M. Clark, Djork-Arné Clevert, Chris A. Dejong, Chao Du, Scarlet Ferrinho, Francesca Grisoni, Albert Hofstetter, Willem Jespers, Olga V. Kalinina, Satria A. Kautsar, Hyunwoo Kim, Tiago F. Leao, Joleen Masschelein, Evan R. Rees, Raphael Reher, Daniel Reker, Philippe Schwaller, Marwin Segler, Michael A. Skinnider, Allison S. Walker, Egon L. Willighagen, Barbara Zdrazil, Nadine Ziemert, Rebecca J. M. Goss, Pierre Guyomard, Andrea Volkamer, William H. Gerwick, Hyun Uk Kim, Rolf Müller, Gilles P. van Wezel, Gerard J. P. van Westen, Anna K. H. Hirsch, Roger G. Linington, Serina L. Robinson, Marnix H. Medema
Journal: Nature Reviews Drug Discovery (2023)
Effect of Metformin Versus Placebo on New Primary Cancers in Canadian Cancer Trials Group MA.32: A Secondary Analysis of a Phase III Randomized Double-Blind Trial in Early Breast Cancer
Authors: Pamela J. Goodwin, Bingshu E. Chen, Karen A. Gelmon, Timothy J. Whelan, Marguerite Ennis, Julie Lemieux, Jennifer A. Ligibel, Dawn L. Hershman, Ingrid A. Mayer, Timothy J. Hobday, Judith M. Bliss, Priya Rastogi, Manuela Rabaglio-Poretti, Alastair M. Thompson, Daniel W. Rea, Paul M. Stos, Lois E. Shepherd, Vuk Stambolic, Wendy R. Parulekar
Journal: Journal of Clinical Oncology (2023)

JCO
Gelatin-based 3D biomimetic scaffolds platform potentiates culture of cancer stem cells in esophageal squamous cell carcinoma
Authors: Yenan Wu, Haiwei Liang, Aiping Luo, Yong Li, Zhiqiang Liu, Xin Li, Wenxin Li, Kaini Liang, Junyang Li, Zhihua Liu, Yanan Du
Journal: Biomaterials (2023)
Inflammatory Activity of Epithelial Stem Cell Variants from Cystic Fibrosis Lungs Is Not Resolved by CFTR Modulators
Authors: Shan Wang, Suchan Niroula, Ashley Hoffman, Melika Khorrami, Melina Khorrami, Feng Yuan, Grace N. Gasser, Soon Choi, Bovey Liu, Justin Li, Mark L. Metersky, Matthew Vincent, Christopher P. Crum, Richard C. Boucher, Harry Karmouty-Quintana, Howard J. Huang, Ajay Sheshadri, Burton F. Dickey, Kalpaj R. Parekh, John F. Engelhardt, Frank D. McKeon, Wa Xian
Journal: American Journal of Respiratory and Critical Care Medicine (2023)

Rationale: "CFTR modulator" drugs restore function to mutant channels in cystic fibrosis (CF) patients and lead to improvements in body-mass index and lung function especially in younger patients. While it is anticipated that early treatment with CFTR modulators will significantly delay the onset of advanced lung disease, lung neutrophils and inflammatory cytokines remain high in modulator-treated CF patients with established lung disease, underscoring the need to identify and ultimately target the source of this inflammation in CF lung. Objectives: To examine the stem cell heterogeneity of CF lung to identify stem cell variants that might underlie the chronic lung inflammation in CF and the impact of CFTR genetic complementation or CFTR modulators on the inflammatory properties of the stem cell variants identified herein. Methods: Stem cell cloning technology was applied to CF lungs. Single cell-derived clones were assessed by RNA-sequencing and xenografting to monitor inflammation, fibrosis, and mucin secretion. The impact of CFTR activity on these variants following gene complementation or exposure to CFTR modulators was assessed by molecular and functional studies. Measurements and Main Results: CF lungs display a stem cell heterogeneity marked by six predominant variants of which three are proinflammatory both at the level of gene expression and their ability to drive neutrophil inflammation in xenografts. The proinflammatory functions of these variants were unallayed by genetic or pharmacological restoration of CFTR activity. Conclusions: The emergence of proinflammatory stem cell variants in CF lung may explain the persistence of lung inflammation in CF patients undergoing CFTR modulator therapy. This article is open access and distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives License 4.0 (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Viral genetic clustering and transmission dynamics of the 2022 mpox outbreak in Portugal
Authors: Vítor Borges, Mariana Perez Duque, João Vieira Martins, Paula Vasconcelos, Rita Ferreira, Daniel Sobral, Ana Pelerito, Isabel Lopes de Carvalho, Maria Sofia Núncio, Maria José Borrego, Cornelius Roemer, Richard A. Neher, Megan O’Driscoll, Raquel Rocha, Sílvia Lopo, Raquel Neves, Paula Palminha, Luís Coelho, Alexandra Nunes, Joana Isidro, Miguel Pinto, João Dourado Santos, Verónica Mixão, Daniela Santos, Silvia Duarte, Luís Vieira, Fátima Martins, Jorge Machado, Vítor Cabral Veríssimo, Berta Grau, André Peralta-Santos, José Neves, Margarida Caldeira, Mafalda Pestana, Cândida Fernandes, João Caria, Raquel Pinto, Diana Póvoas, Fernando Maltez, Ana Isabel Sá, Mafalda Brito Salvador, Eugénio Teófilo, Miguel Rocha, Virginia Moneti, Luis Miguel Duque, Francisco Ferreira e Silva, Teresa Baptista, Joana Vasconcelos, Sara Casanova, Kamal Mansinho, João Vaz Alves, João Alves, António Silva, Miguel Alpalhão, Cláudia Brazão, Diogo Sousa, Paulo Filipe, Patrícia Pacheco, Francesca Peruzzu, Rita Patrocínio de Jesus, Luís Ferreira, Josefina Mendez, Sofia Jordão, Frederico Duarte, Maria João Gonçalves, Eduarda Pena, Claúdio Nunes Silva, André Rodrigues Guimarães, Margarida Tavares, Graça Freitas, Rita Cordeiro, João Paulo Gomes
Journal: Nature Medicine (2023)

Pathogen genome sequencing during epidemics enhances our ability to identify and understand suspected clusters and investigate their relationships. Here, we combine genomic and epidemiological data of the 2022 mpox outbreak to better understand early viral spread, diversification and transmission dynamics. By sequencing 52% of the confirmed cases in Portugal, we identified the mpox virus sublineages with the highest impact on case numbers and fitted them into a global context, finding evidence that several international sublineages probably emerged or spread early in Portugal. We estimated a 62% infection reporting rate and that 1.3% of the population of men who have sex with men in Portugal were infected. We infer the critical role played by sexual networks and superspreader gatherings, such as sauna attendance, in the dissemination of mpox virus. Overall, our findings highlight genomic epidemiology as a tool for the real-time monitoring and control of mpox epidemics, and can guide future vaccine policy in a highly susceptible population.
COLLAGENE enables privacy-aware federated and collaborative genomic data analysis
Authors: Wentao Li, Miran Kim, Kai Zhang, Han Chen, Xiaoqian Jiang, Arif Harmanci
Journal: Genome biology (2023)

Abstract Growing regulatory requirements set barriers around genetic data sharing and collaborations. Moreover, existing privacy-aware paradigms are challenging to deploy in collaborative settings. We present COLLAGENE, a tool base for building secure collaborative genomic data analysis methods. COLLAGENE protects data using shared-key homomorphic encryption and combines encryption with multiparty strategies for efficient privacy-aware collaborative method development. COLLAGENE provides ready-to-run tools for encryption/decryption, matrix processing, and network transfers, which can be immediately integrated into existing pipelines. We demonstrate the usage of COLLAGENE by building a practical federated GWAS protocol for binary phenotypes and a secure meta-analysis protocol. COLLAGENE is available at https://zenodo.org/record/8125935 .
ZINBMM: a general mixture model for simultaneous clustering and gene selection using single-cell transcriptomic data
Authors: Yang Li, Mingcong Wu, Shuangge Ma, Mengyun Wu
Journal: Genome biology (2023)

Abstract Clustering is a critical component of single-cell RNA sequencing (scRNA-seq) data analysis and can help reveal cell types and infer cell lineages. Despite considerable successes, there are few methods tailored to investigating cluster-specific genes contributing to cell heterogeneity, which can promote biological understanding of cell heterogeneity. In this study, we propose a zero-inflated negative binomial mixture model (ZINBMM) that simultaneously achieves effective scRNA-seq data clustering and gene selection. ZINBMM conducts a systemic analysis on raw counts, accommodating both batch effects and dropout events. Simulations and the analysis of five scRNA-seq datasets demonstrate the practical applicability of ZINBMM.
LINC02774 inhibits glycolysis in glioma to destabilize HIF‐1α dependent on transcription factor RP58
Authors: Yuanbing Chen, Yating Liu, Jianbing Xiong, Lianlian Ouyang, Miao Tang, Chao Mao, Liling Li, Desheng Xiao, Shuang Liu, Zhen Yang, Jun Huang, Yongguang Tao
Journal: MedComm (2023)

Glioma, the most common of malignant tumors in the brain, is responsible for the majority of deaths from primary brain tumors. The regulation of long noncoding RNAs (lncRNAs) in HIF-1α-driven tumor development remains unclear. LINC02774 is a nuclear lncRNA and that it is being reported for the first time in this study. We found the downregulation of LINC02774 in glioma and decreased with the degree of malignant, with its expression showing a negative correlation with the relative index of enhanced magnetic resonance (RIEMR). RIEMR-associated LINC02774 was found to inhibit glycolysis by modulating the hypoxia pathway rather than the hypoxia response itself. LINC02774 interacted with its neighboring gene, RP58 (ZBTB18), to enhance the expression of PHD3, which catalyzed HIF-1α hydroxylase and ubiquitination, leading to the downregulation of HIF-1α expression. We also found that the function of LINC02774, dependent on PHD3, was diminished upon RP58 depletion. Notably, higher expression of RIEMR-associated LINC02774 was associated with a favorable prognosis. In conclusion, these findings reveal the role of RIEMR-associated LINC02774, which relies on its neighbor gene, RP58, to regulate the hypoxia pathway as a novel tumor suppressor, suggesting its potential to be a prognostic marker and a molecular target for the therapy of glioma.
Impact of a TLR9 agonist and broadly neutralizing antibodies on HIV-1 persistence: the randomized phase 2a TITAN trial
Authors: Jesper D. Gunst, Jesper F. Højen, Marie H. Pahus, Miriam Rosás-Umbert, Birgitte Stiksrud, James H. McMahon, Paul W. Denton, Henrik Nielsen, Isik S. Johansen, Thomas Benfield, Steffen Leth, Jan Gerstoft, Lars Østergaard, Mariane H. Schleimann, Rikke Olesen, Henrik Støvring, Line Vibholm, Nina Weis, Anne M. Dyrhol-Riise, Karen B. H. Pedersen, Jillian S. Y. Lau, Dennis C. Copertino, Noemi Linden, Tan T. Huynh, Victor Ramos, R. Brad Jones, Sharon R. Lewin, Martin Tolstrup, Thomas A. Rasmussen, Michel C. Nussenzweig, Marina Caskey, Dag Henrik Reikvam, Ole S. Søgaard
Journal: Nature Medicine (2023)

Abstract Inducing antiretroviral therapy (ART)-free virological control is a critical step toward a human immunodeficiency virus type 1 (HIV-1) cure. In this phase 2a, placebo-controlled, double-blinded trial, 43 people (85% males) with HIV-1 on ART were randomized to (1) placebo/placebo, (2) lefitolimod (TLR9 agonist)/placebo, (3) placebo/broadly neutralizing anti-HIV-1 antibodies (bNAbs) or (4) lefitolimod/bNAb. ART interruption (ATI) started at week 3. Lefitolimod was administered once weekly for the first 8 weeks, and bNAbs were administered twice, 1 d before and 3 weeks after ATI. The primary endpoint was time to loss of virologic control after ATI. The median delay in time to loss of virologic control compared to the placebo/placebo group was 0.5 weeks ( P = 0.49), 12.5 weeks ( P = 0.003) and 9.5 weeks ( P = 0.004) in the lefitolimod/placebo, placebo/bNAb and lefitolimod/bNAb groups, respectively. Among secondary endpoints, viral doubling time was slower for bNAb groups compared to non-bNAb groups, and the interventions were overall safe. We observed no added benefit of lefitolimod. Despite subtherapeutic plasma bNAb levels, 36% (4/11) in the placebo/bNAb group compared to 0% (0/10) in the placebo/placebo group maintained virologic control after the 25-week ATI. Although immunotherapy with lefitolimod did not lead to ART-free HIV-1 control, bNAbs may be important components in future HIV-1 curative strategies. ClinicalTrials.gov identifier: NCT03837756 .